[Pulmonary embolism as a presentation of nephrotic syndrome]. / Embolie pulmonaire révélant un syndrome néphrotique.

BACKGROUND: Nephrotic syndrome (NS) in adults is defined by proteinuria>3g/24h or 50mg/kg/d, hypoproteinemia<60g/24h and hypoalbuminemia<30g/L. The final diagnosis is guided by the histopathology evidence when a renal biopsy is possible. The consequences of NS are multiple: high blood pressure, undernutrition, infections and a hypercoagulable state. OBSERVATION: We report the case of a patient presenting with thromboembolic disease, occurring in the absence of other thromboembolic risk factors, which revealed NS with spontaneously favorable evolution. CONCLUSION: Thromboembolic disease in NS is frequent but underestimated and may remain underdiagnosed. Thorough investigation - including serum protein levels and testing for proteinuria - are essential in thromboembolism, as is excluding cancer or another cause. The treatment of thromboembolic disease in NS is based on anticoagulation for as long as the NS persists. There is no consensus about primary prophylaxis but an albumin level below 20g/L should be considered as a risk factor of thrombosis and prophylactic anticoagulation should be started.

Can we continue to neglect genomic variation in introgression rates when inferring the history of speciation? A case study in a Mytilus hybrid zone.

The use of molecular data to reconstruct the history of divergence and gene flow between populations of closely related taxa represents a challenging problem. It has been proposed that the long-standing debate about the geography of speciation can be resolved by comparing the likelihoods of a model of isolation with migration and a model of secondary contact. However, data are commonly only fit to a model of isolation with migration and rarely tested against the secondary contact alternative. Furthermore, most demographic inference methods have neglected variation in introgression rates and assume that the gene flow parameter (Nm) is similar among loci. Here, we show that neglecting this source of variation can give misleading results. We analysed DNA sequences sampled from populations of the marine mussels, Mytilus edulis and M. galloprovincialis, across a well-studied mosaic hybrid zone in Europe and evaluated various scenarios of speciation, with or without variation in introgression rates, using an Approximate Bayesian Computation (ABC) approach. Models with heterogeneous gene flow across loci always outperformed models assuming equal migration rates irrespective of the history of gene flow being considered. By incorporating this heterogeneity, the best-supported scenario was a long period of allopatric isolation during the first three-quarters of the time since divergence followed by secondary contact and introgression during the last quarter. By contrast, constraining migration to be homogeneous failed to discriminate among any of the different models of gene flow tested. Our simulations thus provide statistical support for the secondary contact scenario in the European Mytilus hybrid zone that the standard coalescent approach failed to confirm. Our results demonstrate that genomic variation in introgression rates can have profound impacts on the biological conclusions drawn from inference methods and needs to be incorporated in future studies.

The genetics of speciation: are complex incompatibilities easier to evolve?

Reproductive isolation can evolve readily when genotypes containing incompatible alleles are connected by chains of fit intermediates. Experimental crosses show that such Dobzhansky-Muller incompatibilities (DMIs) are often complex (involving alleles at three or more loci) and asymmetrical (such that reciprocal introgressions have very different effects on fitness). One possible explanation is that asymmetrical and complex DMIs are 'easier to evolve', because they block fewer of the possible evolutionary paths between the parental genotypes. To assess this argument, we model evolutionary divergence in allopatry and calculate the delays to divergence caused by DMIs of different kinds. We find that the number of paths is sometimes, though not always, a reliable predictor of the time to divergence. In particular, we find limited support for the idea that symmetrical DMIs take longer to evolve, but this applies largely to two-locus symmetrical DMIs (which leave no path of fit intermediates). Symmetrical complex DMIs can also delay divergence, but only in a limited region of parameter space. In most other cases, the presence and form of DMIs have little influence on times to divergence, and so we argue that ease of evolution is unlikely to be important in explaining the experimental data.

IL-4 inhibits apoptosis and prevents mitochondrial damage without inducing the switch to necrosis observed with caspase inhibitors.

We previously demonstrated that the broad-spectrum caspase inhibitor, zVAD-fmk, totally deviated apoptosis to necrosis in B lymphocytes. We report here that, in contrast with zVAD-fmk, IL-4 protected B cells from spontaneous and from dexamethasone-induced apoptosis and actually maintained cell viability. This was assessed by morphological and biochemical criteria and accompanied by the maintenance of mitochondrial transmembrane potential (DeltaPsiCm) and elevated glutathione (GSH) levels. Under these conditions, zVAD-fmk also totally inhibited apoptosis in thymocytes, but it partly preserved cell viability with a parallel increase in the percentage of cells exhibiting high DeltaPsiCm and elevated GSH levels. Nevertheless, non-rescued cells were deviated to necrosis. Therefore, the pathway leading to either apoptosis or necrosis appears to involve common mitochondrial dysfunctions which could not be reversed by caspase inhibition, suggesting that the pharmacological inhibition of cell death should occur at an earlier stage.

TNF-alpha activates at least two apoptotic signaling cascades.

Apoptosis, the process whereby cells activate an intrinsic death program, can be induced in HeLa cells by TNF-alpha treatment. The aims of the present study were (i) to examine the precise role and the origin of Reactive Oxygen Species (ROS) in the TNF-alpha-induced programmed cell death, (ii) to characterize and order the morphological and mitochondrial changes associated with this process and (iii) to link these events with the activation of caspases. Analyses were performed on TNF-alpha-treated cells in the presence of an anti-oxidant, or of a general caspase inhibitor. To assess the role of mitochondria in the cell death signal transduction, these studies were also realized on HeLa-variant cell lines lacking functional mitochondrial respiratory chain. We show that at least two separate signaling cascades, both mediated by Z-VAD-sensitive caspase(s), contribute to the TNF-alpha-induced apoptosis of HeLa cells. One signaling pathway involves an early mitochondria-dependent ROS production, the other being ROS-independent.

Bcl-2 and Hsp27 act at different levels to suppress programmed cell death.

Apoptosis and necrosis, two morphologically distinct forms of cell death, can be induced by common stimuli depending on the doses and the cell type. This study compares the protective effect of oncoprotein Bcl-2 and of the small stress protein Hsp27 on these two types of cell death. We use rat embryo fibroblasts conditionally immortalized by the tsA58 mutant of SV40 large T antigen as parental cells to develop cell lines carrying inducible bcl-2 or hsp27 genes. Two apoptotic stimuli were used: shift to the restrictive temperature that induced p53-mediated apoptosis and treatment with low doses of hydrogen peroxide. Necrosis was induced by high doses of hydrogen peroxide. Although Bcl-2 and Hsp27 protect these cells from necrotic death, only Bcl-2 appears capable of preventing apoptotic death. Bcl-2 protection is not mediated by a negative effect on the induction of the p53 responsive genes bax or waf1 but it slows down at least two stages of apoptosis: decrease of mitochondrial membrane potential and subsequent morphological changes. In contrast, although Hsp27 has been recently shown to inhibit apoptosis induced by various stimuli, its overexpression has no effect on apoptosis in this cell system. It should be also noticed that the apoptotic stimuli (temperature shift or hydrogen peroxide treatment) induce Hsp27, but not Bcl-2 accumulation suggesting that, in parental cells, Hsp27 might already provide some protection. However, taken together these results suggest that Hsp27, as well as Bcl-2, acts at several levels to inhibit cell death, but that their protective functions only partially overlap.